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Long non-coding RNA CASC2 suppresses epithelial-mesenchymal transition of hepatocellular carcinoma cells through
Yufeng Wang1, Zhikui Liu1, Bowen Yao1
1Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China.
Background:
Recently, it has been reported that long non-coding RNA (lncRNA) cancer susceptibility candidate 2 (CASC2), a novel tumor suppressor, participates in regulating the carcinogenesis and suppresses tumor progression by sponging microRNAs (miRNAs). However, the expression and function of CASC2 in hepatocellular carcinoma (HCC) remain unclear.
Methods:
The expression of CASC2 and miR-367 in HCC specimens and cell lines were detected by real-time PCR. Western blotting and immunohistochemistry were carried out for detection of epithelial-to-mesenchymal transition (EMT) markers in HCC. Transwell assays were used to determine migration and invasion of HCC cells. A mouse model for lung metastasis was established to evaluated HCC metastasis in vivo. The correlation among CASC2, miR-367 and F-box and WD repeat domain containing 7 (FBXW7) were disclosed by a dual-luciferase reporter assay, RIP assay and biotin pull-down assay.
Results:
Here, CASC2 expression was significantly downregulated in HCC tissues, especially in aggressive and recurrent cases. In accordance, CASC2 underexpression was observed in HCC cell lines compared to LO2. In vitro and in vivo experiments revealed that CASC2 inhibited migration and invasion of HCC cells. Additionally, CASC2 repressed EMT process of HCC cells. Further studies demonstrated that CASC2 could function as a competing endogenous RNA (ceRNA) by sponging miR-367 in HCC cells. Functionally, gain- and loss-of-function studies showed that miR-367 promoted migration, invasion and EMT progression of HCC cells. Moreover, further investigations disclosed that FBXW7 was a downstream target of miR-367 and CASC2 prohibited EMT progression and subsequently exerted its anti-metastatic effects via CASC2/miR-367/FBXW7 axis in HCC cells. Clinically, CASC2 underexpression and miR-367 overexpression were closely correlated with the metastasis-associated clinicopathologic features. Notably, CASC2 low-expressing and miR-367 high-expressing HCC patients showed the poorest clinical outcome.
Conclusions:
Overall, we conclude that the CASC2/miR-367/FBXW7 axis may be a ponderable and promising therapeutic target for HCC.
Insights
Long non-coding RNA CASC2 suppresses hepatocellular carcinoma (HCC) progression by inhibiting miR-367 and its target FBXW7. This CASC2/miR-367/FBXW7 axis represents a promising therapeutic target for HCC patients.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Long non-coding RNA (lncRNA) cancer susceptibility candidate 2 (CASC2) is a novel tumor suppressor.
- CASC2's role in hepatocellular carcinoma (HCC) carcinogenesis and progression is not fully understood.
- CASC2 may function by sponging microRNAs (miRNAs).
Purpose of the Study:
- To investigate the expression and function of CASC2 in HCC.
- To elucidate the molecular mechanism of CASC2 in HCC progression.
- To explore the CASC2/miR-367/FBXW7 axis as a potential therapeutic target for HCC.
Main Methods:
- Real-time PCR, Western blotting, and immunohistochemistry were used to detect CASC2, miR-367, and EMT markers.
- Transwell assays and a mouse metastasis model assessed cell migration, invasion, and metastasis.
- Dual-luciferase reporter, RIP, and biotin pull-down assays identified interactions between CASC2, miR-367, and FBXW7.
Main Results:
- CASC2 was significantly downregulated in HCC tissues and cell lines, correlating with aggressive and recurrent disease.
- CASC2 inhibited HCC cell migration, invasion, and epithelial-to-mesenchymal transition (EMT).
- CASC2 acted as a competing endogenous RNA (ceRNA) for miR-367, targeting FBXW7, thereby suppressing EMT and metastasis.
Conclusions:
- The CASC2/miR-367/FBXW7 axis plays a critical role in HCC progression.
- CASC2 downregulation and miR-367 upregulation are associated with poor clinical outcomes in HCC.
- This axis represents a promising therapeutic target for hepatocellular carcinoma.
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